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Obesity is a fibroblast growth factor 21 (FGF21)-resistant state
Ffolliott M Fisher1, Patricia C Chui, Patrick J Antonellis
1Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Objective:
Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity.
Research Design And Methods:
To test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21.
Results:
When obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice.
Conclusions:
These data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.
Insights
Obesity leads to resistance to Fibroblast Growth Factor 21 (FGF21), despite elevated FGF21 levels. Obese mice show impaired responses to FGF21, suggesting a FGF21-resistant state in obesity.
Area of Science:
- Metabolism and endocrinology research.
- Molecular mechanisms of metabolic regulation.
Background:
- Fibroblast Growth Factor 21 (FGF21) regulates fatty acid oxidation and lipid metabolism.
- Pharmacological FGF21 aids weight loss and improves glucose tolerance in mice.
- Paradoxically, FGF21 levels are high in obesity, yet its beneficial effects are diminished.
Purpose of the Study:
- To investigate if obesity induces FGF21 resistance.
- To assess FGF21 signaling and transcriptional responses in diet-induced obesity (DIO).
- To analyze the physiological impact of FGF21 resistance in obese mice.
Main Methods:
- Evaluating obese mouse response to exogenous FGF21.
- Assessing FGF21 signaling via ERK1/2 phosphorylation in liver and adipose tissue.
- Analyzing FGF21 target gene induction (cFos, EGR1) and serum parameters.
Main Results:
- Obese mice exhibited attenuated ERK1/2 phosphorylation in response to FGF21.
- Impaired induction of FGF21 target genes (cFos, EGR1) was observed in liver and fat.
- Declines in glucose and free fatty acids were attenuated in FGF21-treated DIO mice.
Conclusions:
- Diet-induced obese mice display elevated endogenous FGF21 levels.
- These mice show a poor response to exogenous FGF21 administration.
- Obesity is characterized as a state of FGF21 resistance.
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